Synthesis, characterization and in vitro anticancer evaluations of two novel derivatives of deferasirox iron chelator

Iron (Fe) chelation therapy was initially designed to alleviate the toxic effects of excess Fe evident in Fe-overload diseases. However, the novel toxicological properties of some Fe chelator-metal complexes have shifted significant attention to their application in cancer chemotherapy. The present study investigates the new role of deferasirox as an anticancer agent due to its ability to chelate with iron. Because of aminoacids antioxidant effect, deferasirox and its two novel amino acid derivatives have been synthesized through the treatment of deferasirox with DCC as well as glycine or phenylalanine methyl ester. All new compounds have been characterized by elemental analysis, FT-IR NMR and mass spectrometry. Therefore, the cytotoxicity of these compounds was screened for antitumor activity against some cell lines using cisplatin as a comparative standard by MTT assay and Flow cytometry. The impact of iron in the intracellular generation of reactive oxygen species was assessed on HT29 and MDA-MB-231 cells. The potential of the synthesized iron chelators for their efficacy to protect cells against model oxidative injury induced was compared. The reactive oxygen species intracellular fluorescence intensity were measured and the result showed that the reactive oxygen species intensity after iron incubation increased while after chelators incubation the reactive oxygen species intensity were decreased significantly. Besides, the effect of the synthesized compounds on mouse fibroblast cell line (L929) was simultaneously evaluated as control. The pharmacological results showed that deferasirox and its two novel aminoacid derivatives were potent anticancer agents.

The role of iron in ROS metabolism and iron chelators antiproliferative activity mechanism. The reaction of peroxides with Fe2+ to yield soluble hydroxyl (HO
• ) radicals is referred to as the Fenton reaction. Key enzymes that contribute to ROS formation or detoxifiation are shown. Those whose function is iron dependent are colored blue, and the relevant iron species is in parentheses. Clinical iron chelator such as deferasirox are used to enter tumor cells and bind intracellular iron, depriving these cells of this important metal and stop the tumor growth.Figure optionsDownload high-quality image (154 K)Download as PowerPoint slide